Neurological complications associated with influenza in hospitalized children

Abstract Background Influenza is a known respiratory and potential neurotropic virus. This study aimed to determine the prevalence and outcomes of influenza‐related neurological complications among hospitalized children. Methods All medical records of hospitalized children aged <18 years old diagnosed with influenza at a tertiary care hospital in Bangkok were retrospectively reviewed. Influenza infection was confirmed by rapid antigen or reverse transcription polymerase chain reaction tests. Neurological characteristics and clinical outcomes were analyzed using the Pediatric Cerebral Performance Category Scale. Results From 2013 to 2018, 397 hospitalized children with a median age of 3.7 years (interquartile range [IQR]: 1.6–6.9) were included. The prevalence of neurological complications, including seizure or acute encephalopathy, was 16.9% (95% confidence interval [CI]: 13.3–20.9). Influenza A and B were identified in 73.1% and 26.9% of the patients, respectively. Among 39 (58.2%) acute symptomatic seizure cases, 25 (37.3%) children had simple febrile seizures, 7 (10.4%) had repetitive seizures, and 7 (10.4%) had provoked seizures with pre‐existing epilepsy. For 28 (41.8%) encephalopathy cases, the clinical courses were benign in 20 (29.9%) cases and severe in 8 (11.9%) cases. Ten (14.9%) children needed intensive care monitoring, and 62 (93.5%) fully recovered to their baselines at hospital discharge. Predisposing factors to the neurological complications included a history of febrile seizure (adjusted odds ratio [aOR]: 20.3; 95% CI: 6.6–63.0), pre‐existing epilepsy (aOR: 3.6; 95% CI: 1.3–10.2), and a history of other neurological disorders (aOR: 3.5; 95% CI: 1.2–10.2). Conclusions One fifth of hospitalized children with influenza had neurological complications with a favorable outcome. Children with pre‐existing neurological conditions were at higher risk for developing neurological complications.


| BACKGROUND
Influenza is a common contagious respiratory virus that primarily causes upper and lower respiratory tract infections. The virus is estimated to infect 9 to 45 million people yearly, mainly young children. 1 Typical clinical presentations in children include high fever and gastrointestinal conditions such as reduced appetite, nausea, and vomiting. 2,3 Moreover, influenza can accompany neurological complications in up to 10-30% of pediatric patients. [4][5][6] The common neurological symptoms in children are seizures and encephalopathy, with variable severities. 7 In general, seizures are more common 8 ; however, in Asian countries, encephalopathy has been reported with increasing frequencies. [9][10][11] Furthermore, encephalopathy is likely to result in more severe sequelae than febrile seizures. 12 Other neurological complications include meningitis, stroke, acute disseminated encephalomyelitis (ADEM), and Guillain-Barré syndrome. 7,13 Various studies reported that the mortality rate varied from 7% to around 30%. 9,14,15 Though most children experienced no sequelae, 5,7,10 up to 10% of hospitalized children with influenza might have neurological abnormalities at discharge or up to 40% in cases of severe complications. 5,14 Clinical sequelae or persistent disabilities can be acute necrotizing encephalopathy (ANE), myelitis, and meningitis. 14,16,17 In previous studies, possible risk factors included a history of febrile seizure, genetic predisposition in other family members, and pre-existing neurological disease. 5,13,17 In tropical countries, seasonal influenza outbreaks can occur annually or biannually, whereas seasonal outbreaks during winter are more common in Arctic countries. 18 In Thailand, biannual outbreaks were recorded during the rainy and winter seasons, with the major incidence from August to September. 18 According to Department of Public Health Thailand data, children under 5 years old were at the highest risk of getting influenza, followed by those between 5 and 14 years old.
However, there were limited reports on influenza-associated neurological complications in Thailand, so this study primarily aimed to determine the prevalence and outcomes of neurological complications associated with influenza among hospitalized children and secondarily aimed to assess factors related to influenza-related neurological complications.

| METHODS
This study was a retrospective medical record review in a tertiary care center, King Chulalongkorn Memorial Hospital (KCMH), Bangkok, Thailand, which has a capacity of 300 beds for children. The study included hospitalized children aged 1 month to less than 18 years old who were diagnosed with influenza from January 2013 to December 2018 and had any neurological signs or symptoms. The cases were identified by the ICD-10 coding of J09-J11 influenza group, and G02, G04, and G05. All electronic medical records of these patients were reviewed for demographic data, clinical diagnosis, treatment, and outcomes using the Pediatric Cerebral Performance Category (PCPC) Scale. 19 In addition, cases with neurological complications were retrospectively reviewed by two pediatric neurologists (TaP and KC). The study was approved by the Institutional Review Board (IRB) of the

| A review of medical records
Data extraction from medical records was as follows: demographic data, admission unit, underlying medical conditions, clinical characteristics of neurological symptoms and other symptoms, a history of influenza vaccination, influenza virus subtypes, treatments, duration of admission, and clinical outcomes at discharge and 6 months after diagnosis, which were assessed by the PCPC Scale 19,20 (Appendix A). In addition, brain imaging, including computed tomography (CT) and/or magnetic resonance imaging (MRI), was reviewed by a neuroradiologist (TuP).

| Case definition of neurological complications
The neurological complications were defined as having either seizure or acute encephalopathy. 7,21 The seizure was further categorized into a provoked seizure in children with underlying epilepsy and new onset of seizure with the following characteristics: (1) generalized seizure (defined as non-focal seizures without underlying seizure disorder, brain abnormality, or other significant metabolic diseases), (2) repetitive seizure (defined as multiple seizures), or (3) status epilepticus (defined as continuous seizure activity lasting longer than 5 min for generalized seizure and longer than 10 min for focal seizures). 22 23,24 Any children who had a seizure with subsequent alternation of consciousness of more than 24 h were categorized into an acute encephalopathy group.  symptoms. Therefore, clinical suspicion and awareness of influenza infections were essential, despite the complete typical manifestations.

| Clinical characteristics of neurological complications
The clinical manifestations of influenza-associated neurological complications can vary, from mild symptoms such as headache, numbness, and drowsiness to more moderate and severe symptoms such as seizure and acute encephalopathy. 7 Moreover, the severity of a seizure can be a single episode of seizure, repetitive seizures, or status epilepticus. The definite pathophysiology of the neurological complications remains unclear, whether they are due to direct viral invasion or immunological or inflammatory responses. 32,33 In this study, there was no evidence of direct viral invasion from the RT-PCR for influenza from the CSF, so the children with severe encephalopathy cases were treated with methylprednisolone aiming to mediate the immunological responses.
Typical imaging findings of influenza-associated neurological complications have been reported using the terms of clinico-radiological diagnosis. 10,30,31,[34][35][36] In this study, several clinico-radiological diagnostic terms were applied, including ANE, MERS, and a rare form of isolated brainstem leukoencephalopathy (Table 3). However, there are also some other reported lesions, for example, the lesion in the pons. 37 Notably, though the aforementioned clinico-radiological findings have been reported in association with influenza, similar findings can also be found in other infections. 34,[38][39][40] In this study, four patients had electroencephalographic findings of focal epileptiform activities, representing the central nervous system inflammation.
Most children in this study (93%) had complete or nearly complete recovery at discharge. Some children took 6 months following diagnosis to full recovery. One case was diagnosed with ANE and experienced long-term neurological deficits. 24,34,41,42 As cytokine storms and genetic mutation in RAN binding protein 2 (RANBP2) gene may be responsible for the pathogenesis of severe encephalopathy, including ANE, the use of methylprednisolone is likely beneficial for treating cytokine storm and metabolic dysfunction by decreasing inflammation, providing protective regulatory effects on mitochondria and limiting the extent of brain edema. 34,43 In this study, children with acute encephalopathy were treated with methylprednisolone and had good responses. However, mild encephalopathy is generally self-limited. In this study, two patients had the distinct form of white matter lesions, MERS, and acute brain stem leukoencephalopathy. Patients with MERS were reported to have a good prognosis 36 ; however, one child with MERS in our study presented a marked alteration of consciousness with complete recovery. Another rare presentation in our children included acute brain stem leukoencephalopathy, in which her presenting neurological deficits were debilitating. With intravenous methylprednisolone treatment, the child had got complete recovery.
Predisposing factors of influenza-associated neurological complications included previous neurological disorders such as febrile convulsion, which is the most powerful, epilepsy, and other neurological diseases, consistent with previous studies. 8,10,26,28 Age was also another important factor. Children less than 5 years old tend to have seizure symptoms more than older ones. Regarding the virus types, influenza A is more associated with neurological complications than influenza B. 44

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

ETHICS APPROVAL STATEMENT
The study was approved by the Institutional Review Board (IRB) of the Faculty of Medicine, Chulalongkorn University, and was conducted under the tenets of the Declaration of Helsinki.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13075.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.